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BackgroundClinical scores to determine early (6-month) antiretroviral therapy (ART) mortality risk have not been developed for sub-Saharan Africa (SSA), home to 70% of people living with HIV. In the absence of validated scores, WHO eligibility criteria (EC) for ART care intensification are CD4 MethodsWe used Botswana XPRES trial data for adult ART enrollees to develop CD4-independent and CD4-dependent multivariable prognostic models for 6-month mortality. Scores were derived by rescaling coefficients. Scores were developed using the first 50% of XPRES ART enrollees, and their accuracy validated internally and externally using South African TB Fast Track (TBFT) trial data. Predictive accuracy was compared between scores and WHO EC.ResultsAmong 5553 XPRES enrollees, 2838 were included in the derivation dataset; 68% were female and 83 (3%) died by 6 months. Among 1077 TBFT ART enrollees, 55% were female and 6% died by 6 months. Factors predictive of 6-month mortality in the derivation dataset atp 37.5 °C (2 points). The same variables plus CD4 ConclusionsSensitivity of the CD4-independent score was nearly twice that of WHO stage in predicting 6-month mortality and could be used in settings lacking CD4 testing to inform ART care intensification. The CD4-dependent score improved specificity versus WHO EC. Both scores should be considered for scale-up in SSA.

Background Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. Methods At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. Results We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/μL in SOC, 246/μL in EC, and 241/μL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61–0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. Conclusions Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. Trial registration Retrospectively registered: ClinicalTrials.gov (NCT02538952)

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Background The B.1.1.7 (Alpha) SARS-CoV-2 variant of concern was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between the B.1.1.7 lineage infection and increased 28-day mortality. However, to date none have addressed the impact of infection on severity of illness or the need for oxygen or ventilation. Methods In this prospective clinical cohort sub-study of the COG-UK consortium, 1475 samples from hospitalised and community cases collected between the 1st November 2020 and 30th January 2021 were collected. These samples were sequenced in local laboratories and analysed for the presence of B.1.1.7-defining mutations. We prospectively matched sequence data to clinical outcomes as the lineage became dominant in Scotland and modelled the association between B.1.1.7 infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no support, 2. oxygen, 3. ventilation and 4. death. Additionally, we calculated an estimate of the growth rate of B.1.1.7-associated infections following introduction into Scotland using phylogenetic data. Results B.1.1.7 was responsible for a third wave of SARS-CoV-2 in Scotland, and rapidly replaced the previously dominant second wave lineage B.1.177) due to a significantly higher transmission rate (∼5 fold). Of 1475 patients, 364 were infected with B.1.1.7, 1030 with B.1.177 and 81 with other lineages. Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (B.1.1.7 versus non-B.1.1.7). Viral load was higher in B.1.1.7 samples than in non-B.1.1.7 samples as measured by cycle threshold (Ct) value (mean Ct change: -2.46, 95% CI: -4.22, -0.70). Conclusions The B.1.1.7 lineage was associated with more severe clinical disease in Scottish patients than co-circulating lineages. Funding COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. Funding was also provided by UKRI through the JUNIPER consortium (grant number MR/V038613/1). Sequencing and bioinformatics support was funded by the Medical Research Council (MRC) core award (MC UU 1201412).

Purpose The purpose of this paper is to explore the impact of media coverage on offenders convicted of occupational fraud and corruption in the UK. It examines the extent of media coverage and provides insights into the experiences of offenders. Design/methodology/approach The study is based upon interviews with 17 convicted offenders, and on a content analysis of one national and two regional newspapers in the UK. Findings The findings suggest that offenders convicted of occupational crime and corruption are more likely to experience media coverage than previously assumed and that personal digital criminal legacies create long-term labels which lead to economic strains and social fractures that hinder productive reintegration into society. Research limitations/implications The research is limited by a small sample frame in the UK. Nevertheless, the findings suggest further research is required as they have important implications for privacy and rehabilitation. Practical implications In particular, offenders and their families need support in dealing with their personal digital criminal legacies, accessing their privacy rights and coping with the strains created by online stigmatisation. From a policy perspective, the existing regulatory framework that supports rehabilitation in the UK, especially the increasingly archaic Rehabilitation of Offenders Act 1974, requires close examination and debate to ensure it is fit for the digital era. The findings also suggest that policies, practices and responsibilities of the public sector in employing offenders need to be examined. Originality/value It is a rare study of white-collar offenders after their release from prison. The findings are of relevance to criminal justice policy makers, rehabilitation services and academics.

ObjectivesPatients requiring haemodialysis are at increased risk of serious illness with SARS-CoV-2 infection. To improve the understanding of transmission risks in six Scottish renal dialysis units, we utilised the rapid whole-genome sequencing data generated by the COG-UK consortium.MethodsWe combined geographical, temporal and genomic sequence data from the community and hospital to estimate the probability of infection originating from within the dialysis unit, the hospital or the community using Bayesian statistical modelling and compared these results to the details of epidemiological investigations.ResultsOf 671 patients, 60 (8.9%) became infected with SARS-CoV-2, of whom 16 (27%) died. Within-unit and community transmission were both evident and an instance of transmission from the wider hospital setting was also demonstrated.ConclusionsNear-real-time SARS-CoV-2 sequencing data can facilitate tailored infection prevention and control measures, which can be targeted at reducing risk in these settings.

Background Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV–TB care. Methods and findings We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/μL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/μL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) 10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. Conclusions The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV–TB care to maximize impact of available resources., Andrew Auld and colleagues evaluate a clinical score for active tuberculosis in persons with HIV infection., Author summary Why was this study done? Tuberculosis (TB) remains the most common cause of death among people living with HIV (PLHIV) and is often undiagnosed at time of death. Rapid scale-up of tuberculosis preventive therapy (TPT) to 13 million PLHIV in low- and middle-income countries (LMICs) has been proposed for 2021; however, active TB is commonly asymptomatic and therefore missed by current WHO-recommended 4-symptom TB screening rules. Therefore, more sensitive TB screening tools are needed to better facilitate early TB diagnosis and safer scale-up of TPT to PLHIV by avoiding TPT prescription to clients with asymptomatic active TB, who need TB treatment. What did the researchers do and find? We derived a TB risk score for PLHIV from XPRES trial data and validated the score on 3 external datasets. We prioritized high sensitivity and ability to correctly rule out TB (i.e., high negative predictive value (NPV)) at key time points in care such as HIV clinic enrollment and before TPT prescription. Both logistic regression and random forest machine learning approaches were used to identify the 6 most important predictors, commonly available in LMIC clinic settings. In the external datasets, TB risk score ≥2 had higher sensitivity (87% to 97%) than WHO 4-symptom screening rule and increased NPV by 0.3% to 1.7%. Three risk groups were identified by the score, with active TB prevalence in external datasets ranging from 1% to 6% in the lowest to 22% to 32% in the highest risk groups. What do these findings mean? Following further validation, this clinical score could improve early detection of active TB to reduce morbidity and mortality from undiagnosed TB. Use of the clinical score cutoff of ≥2 during the proposed TPT scale-up for 13 million PLHIV could potentially avoid many thousands of PLHIV with active TB being inappropriately prescribed TPT. By differentiating 3 risk groups, the score also allows for the development of differentiated service delivery models suitable for LMIC.

Corruption of all types including occupational corruption causes immense damage to society. Though a number of guides have been published which offer prevention advice, there is very little original criminological research which connects theory to best practice. This paper demonstrates that Clarke’s situational crime prevention framework provides a mechanism for operatively analysing specific situations to design and implement prevention methods. The study analyses a variety of techniques, based upon a survey and interviews with counter-corruption professionals, to offers insights into their utilisation and effectiveness. To achieve meaningful implementation of the techniques, counter-corruption managers need the delegated power and support of the executive leadership.

This paper explores some of the key barriers to Open Government Data (OGD) that responsible civil servants in the UK face as they try to comply with the UK-led OGD initiative. Empirically, we provide a quantitative analysis of the resources published on the government’s central OGD portal, data.gov.uk, and a unique insight into the publishing of OGD in the UK based on 22 interviews with responsible individuals at the operational level of publishing OGD. Our findings reveal that while the barriers to open government information have been substantially reduced, the barriers to open government data persist. Even the most enthusiastic responsible individuals face considerable obstacles in publishing OGD. Further, a key barrier to OGD in the UK is its impression management strategy based on its informational rather than data orientation. Due to the UK’s pioneering position in the OGD initiative, these findings are relevant to understanding and improving OGD programmes at local, national and international levels. The findings may subsequently lead to evidence-based strategies and policies.

Objective Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit. Design A 36-month double-blind placebo controlled trial (1 : 1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011. Methods One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months. Results In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period. Conclusion The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings.

Setting Although approximately 0.5 million cases of multidrug-resistant tuberculosis (MDR-TB) occur globally each year, surveillance data are limited. Botswana is one of the few high TB burden countries to have carried out multiple anti-tuberculosis drug resistance surveys (in 1995-1996, 1999 and 2002). Objective In 2007-2008, we conducted the fourth national survey of anti-tuberculosis drug resistance in Botswana to assess anti-tuberculosis drug resistance, including trends over time. In the previous survey, 0.8% (95%CI 0.4-1.5) of new patients and 10.4% (95%CI 5.6-17.3) of previously treated patients had MDR-TB. Design During the survey period, eligible specimens from all new sputum-smear positive TB patients and from all TB patients with history of previous anti-tuberculosis treatment underwent mycobacterial culture and anti-tuberculosis drug susceptibility testing (DST). Results Of 924 new TB patients and 137 with previous anti-tuberculosis treatment with DST results, respectively 23 (2.5%, 95%CI 1.6-3.7) and 9 (6.6%, 95%CI 3.3-11.7) had MDR-TB. The proportion of new TB patients with MDR-TB has tripled in Botswana since the previous survey. Conclusion Combatting drug-resistant TB will require the scale-up of MDR-TB diagnosis and treatment to prevent the transmission of MDR-TB and strengthening of general TB control to prevent the emergence of resistance.

An outer shield breach is the most common form of damage that can occur to a subsea flexible pipe during both installation and operation. Definitive and accurate detection and location of such damage is imperative in triggering the appropriate repair response. The overall aim is to minimise corrosion damage to the carbon steel strength elements in the pipe annulus, which occurs from the resulting ingress of seawater. GE Oil & Gas, in collaboration with Photon Fire Ltd have developed a new method of detecting seawater in a subsea flexible pipe annulus. This paper describes a novel breach detection system developed to monitor pipes using very low energy electrical signals appropriate for use in hazardous areas. The technique provides an enduring record of the occurrence of a breach and the extent of the subsequent flooding. A brief outline of the development programme is presented. The work involved determining the sensing technique used, development of appropriate electronic instrumentation, the optimised method for installing the sensor into the riser, and bespoke connection to the instrumentation. A prototype system, approved for use in Hazardous Area ATEX zone zero has been implemented on midscale pipe samples and the transient and steady state ‘scans’ of the pipe have been investigated. A summary of the test results and a proposed testing regime is presented. Results show that using this technique can accurately determine that a breach has occurred in the wall of the riser and the extent of the flooding.

PurposeThis paper aims to give guidance on the level of service charges that can be claimed by residents in sheltered housing as part of their housing benefit claims.Design/methodology/approachThe paper reviews the relevant legislation and recent opinions and rulings of both the Upper Tribunal and the Supreme Court.FindingsA broad based non arithmetical approach must be taken, particularly as many key words are not statutorily defined.Originality/valueClaimants, advocates and decision makers should use the guidance outlined when considering housing benefit claims by sheltered housing residents.

On November 5, 2009, a US Army psychiatrist allegedly opened fire with one or more handguns, killing 12 military personnel and one civilian at Fort Hood in Killeen, Texas. The most severely wounded casualties were transported to Scott and White Memorial Hospital, a Level I trauma center and tertiary care teaching hospital in Temple, Texas associated with the Texas A&M University College of Medicine. Ten victims arrived in a 1-h period with another two arriving in the second hour, necessitating an emergency response to a mass casualty event. Our radiology department's response was largely unplanned and was therefore the result of many spontaneous actions and ideas. We share our experiences and from them formulate guidelines for a general radiology surge model for mass casualty events. It is our hope to raise awareness and help other radiology departments to prepare for such an unexpected event.

Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in the period after the occurrence of a first cardiovascular event. In TNT, 10,001 patients with stable coronary heart disease received double-blind therapy with atorvastatin 80 or 10 mg and were followed for 4.9 years. Post hoc time-to-event analysis was used to estimate separate hazard ratios for time to any first, second, third, fourth, and fifth recurrent cardiovascular events. During TNT, 3,082 patients had a first recurrent cardiovascular event, with 1,516, 698, 345, and 197 developing second, third, fourth, and fifth recurrent events, respectively. In patients receiving atorvastatin 80 mg, the relative risk of a first recurrent event was significantly decreased compared to those receiving atorvastatin 10 mg. Significant benefit with the 80-mg dose was also observed for second, third, fourth, and fifth recurrent events. Similar findings were recorded in 5,854 patients with type 2 diabetes mellitus and/or metabolic syndrome and in 3,809 patientsor = 65 years of age compared to younger patients. In conclusion, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. In TNT, analyses limited to the primary end point significantly underestimated the decrease in total cardiovascular disease burden achieved by intensive low-density lipoprotein cholesterol lowering.

Mycobacterium tuberculosis(TB) affecting the elbow joint is rarely reported in the developed world. We present the case of an 85-year-old Caucasian female who complained of a chronically discharging and painful wound across her left elbow during her admission for an ischaemic stroke. This was initially deemed to be either a bursitis or local manifestation of amyloid by her general practitioner and dermatologist respectively prior to admission. She was commenced on flucloxacillin by the medical team for presumed cellulitis with minimal response. A synovial fluid sample and repeated wound swabs yielded no growth from routine bacterial culture. Radiological assessment together with knowledge of her husband having previous TB raised the possibility of TB arthritis. Synovial fluid aspirate was subsequently sent for acid–alcohol fast bacilli microscopy and mycobacterial culture that confirmed M. tuberculosis. She was consequently started on multidrug TB therapy, over a year after the onset of her symptoms.

Background Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1.8 mmol/L ( = 1.8 mmol/L or

OBJECTIVES: The aim of this post hoc analysis from the TNT (Treating to New Targets) trial is to determine whether patients with previous coronary artery bypass grafting (CABG) surgery achieved clinical benefit from intensive low-density lipoprotein (LDL)-cholesterol lowering. BACKGROUND: The development and progression of atherosclerosis is accelerated in coronary venous bypass grafts. METHODS: A total of 10,001 patients with documented coronary disease, including 4,654 with previous CABG, were randomized to atorvastatin 80 or 10 mg/day and were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event (cardiac death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke). RESULTS: A first major cardiovascular event occurred in 11.4% of the patients with prior CABG and 8.5% of those without prior CABG (p < 0.001). In CABG patients, mean LDL-cholesterol levels at study end were 79 mg/dl in the 80-mg arm and 101 mg/dl in the 10-mg arm, and the primary event rate was 9.7% in the 80-mg arm and 13.0% in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.62 to 0.87, p = 0.0004). Repeat revascularization during follow-up, either CABG or percutaneous coronary intervention, was performed in 11.3% of the CABG patients in the 80-mg arm and 15.9% in the 10-mg arm (hazard ratio 0.70, 95% confidence interval 0.60 to 0.82, p < 0.0001). CONCLUSIONS: Intensive LDL-cholesterol lowering to a mean of 79 mg/dl with atorvastatin 80 mg/day in patients with previous CABG reduces major cardiovascular events by 27% and the need for repeat coronary revascularization by 30%, compared with less intensive cholesterol-lowering to a mean of 101 mg/dl with atorvastatin 10 mg/day. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691)

Intensive Lipid Lowering With Atorvastatin in Patients With Coronary Heart Disease and Chronic Kidney Disease: The TNT (Treating to New Targets) Study James Shepherd, John J. P. Kastelein, Vera Bittner, Prakash Deedwania, Andrei Breazna, Stephen Dobson, Daniel J. Wilson, Andrea Zuckerman, Nanette K. Wenger, for the TNT (Treating to New Targets) Investigators In 9,656 patients with stable coronary heart disease (CHD) and low-density lipoprotein cholesterol levels

In the West of Scotland Coronary Prevention Study (WOSCOPS), treatment of hypercholesterolemic men with pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, reduced their likelihood to progress to diabetes mellitus by 30%. However, the mechanism of this effect of pravastatin has not been investigated. In the current study, we examined the effect of pravastatin on the development of diabetes in obese diabetic mice, and on the insulin-induced glucose uptake and adiponectin production. Pravastatin treatment attenuated the development of diabetes in db/db and high fat/high sucrose diet-fed C57BL/6J mice. An in vivo glucose transport assay showed that pravastatin upregulated glucose uptake in adipose tissue. Insulin-stimulated glucose uptake was enhanced in primary adipocytes isolated from pravastatin-treated mice. Pravastatin treatment increased adiponectin production in 3T3-L1 adipocytes. Plasma adiponectin levels were significantly increased in pravastatin-treated mice. Analyses of plasma samples from the WOSCOPS biobank indicated a significant increase of plasma adiponectin levels with pravastatin treatment (placebo -0.28+/-0.34 microg/ml versus pravastatin +1.47+/-0.33 microg/ml, p=0.0003). Taken together, our findings suggest that pravastatin may have beneficial effects on adipose tissue, which may partly explain the reduction of the development of diabetes by pravastatin treatment.

BACKGROUND: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. METHODS: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. RESULTS: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P

Objectives We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with these polymorphisms could be reduced by pravastatin treatment. Background Identification of genetic polymorphisms associated with CHD may improve assessment of CHD risk and understanding of disease pathophysiology. Methods We tested the association between genotype and recurrent MI in the CARE study and between genotype and primary CHD in the WOSCOPS trial using regression models that adjusted for conventional risk factors: Cox proportional hazards models for the CARE study and conditional logistic regression models for a nested case-control study of the WOSCOPS trial. Results We found that Trp719Arg (rs20455) in KIF6 was associated with coronary events. KIF6 encodes kinesin-like protein 6, a member of the molecular motor superfamily. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had a hazard ratio of 1.50 (95% confidence interval [CI] 1.05 to 2.15) in the CARE trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial. Conclusions In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.

OBJECTIVE: To determine the influence of apolipoproteinEoncognitivedeclineinacohortofelderlymenandwomen.DESIGN: Prospective study.SETTING: Scotland, Ireland, and the Netherlands.PARTICIPANTS: Five thousand eight hundred four subjectsaged70to 82fromtheProspectiveStudy of PravastatinintheElderly at Risk (PROSPER).MEASUREMENTS: Subjects were assessed at baselineand over a mean 3.2-year (range 0.7–4.2) follow-upfor memory (Picture-Word Recall), speed of informationprocessing (Stroop and Letter-Digit Coding), global cogni-tive function (Mini-Mental State Examination), and activ-ities of daily living.RESULTS: At baseline, subjects with apolipoprotein E

BACKGROUND AND OBJECTIVES: Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of or = 60 ml/min per 1.73 m2 in significantly more patients and declined to < 60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm. CONCLUSIONS: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related

Summary Background Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease. Methods We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS. Findings Mean telomere length decreased with age by 9% per decade (95% CI 3·6–14·1; p=0·001) in controls; much the same trend was seen in cases (−5·9% per decade, −3·1 to 14·1; p=0·1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1·51, 95% CI 1·15–1·98; p=0·0029 in the middle tertile; 1·44, 1·10–1·90, p=0·0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1·93, 1·33–2·80, p=0·0005 in the middle tertile; 1·94, 1·33–2·84, p=0·0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1·12, 0·75–1·69, p=0·5755 in the middle tertile; 1·02, 0·68–1·52, p=0·9380 in the lowest). Interpretation Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk—and variability in age of onset—of coronary heart disease.

Aims To investigate the impact of intensive lipid-lowering with high-dose atorvastatin on the cardiovascular risk associated with individual metabolic syndrome components [high body mass index (BMI), elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, hypertension and elevated fasting glucose] in patients with coronary heart disease (CHD). Methods Patients with clinically evident, stable CHD and low-density lipoprotein (LDL) cholesterol

Purpose– The purpose of this paper is to explore the challenges of measuring fraud in overseas aid.Design/methodology/approach– The research is based on 21 semi-structured interviews with key persons working in the delivery of aid in both the public and voluntary sectors. It uses the UK Department for International Development as a case study to applying more accurate measures of fraud.Findings– This paper shows there are significant challenges to using fraud loss measurement to gauge fraud in overseas aid. However, it argues that, along with other types of measures, it could be used in areas of expenditure in overseas governments and charities to measure aid. Given the high risk of such aid to fraud, it argues helping to develop capacity to reduce aid, of which measuring the size of the problem is an important part; this could be considered as aid in its own right.Research limitations/implications– The researchers were not able to visit high-risk countries for fraud to examine in the local context views on the challenges of measuring fraud.Practical implications– The paper offers insights on the challenges to accurately measuring fraud in an overseas context, which will be useful to policy-makers in this context.Social implications– Given the importance of as much aid as possible reaching recipients, it offers an important contribution to helping to reduce losses in this important area.Originality/value– There has been very little consideration of how to measure fraud in the overseas aid context, with most effort aimed at corruption, which poses some of the same challenges, as well as some very different challenges.

Purpose – The purpose of this paper is to provide evidence on the additional costs of dealing with staff fraud, beyond the initial fraud loss, based on 45 cases of staff fraud. Design/methodology/approach – The research began with a “brainstorming” session with counter fraud professionals to map all potential costs in a staff fraud. It then utilised a twin-track approach of a survey and interviews. A survey was distributed using a number of methods yielding 28 usable cases. Interviews were also sought with organisations willing to discuss staff fraud, which secured a further 17 cases. Both the survey and interview used the same questionnaire, although the latter enabled a deeper questioning of participants. Findings – This study examined 45 cases of staff fraud from a wide range of sectors drawn predominantly from larger organisations. From each of these cases detailed, estimates of the costs of dealing with the fraud were identified. Major additional costs included the costs of investigation, staff suspensions, internal disciplinary costs, external sanctions, permanent staff replacement, miscellaneous costs as well as intangible costs. The findings identified significant costs which are significantly above the initial value of the fraud, particularly on initial frauds under £25,000. Research limitations/implications – Staff fraud is a very sensitive subject with many organisations unwilling to reveal what happens when it occurs. The approach was therefore to secure as much data as possible and as such this might not be representative of the broader economy. Practical implications – The paper highlights the need for greater investment in prevention given the substantial costs of staff fraud to deal with. Originality/value – This is the first attempt to gauge the full costs of staff fraud to an organisation.

OBJECTIVE—The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS—A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of RESULTS—End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58–0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48–0.98], P = 0.037) and any cardiovascular event (0.85 [0.73–1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS—Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

Although diabetes is a major cause of chronic kidney disease (CKD), limited data describe the cardiovascular benefit of hydroxymethyl glutaryl CoA reductase inhibitors (statins) in people with both of these conditions. This study sought to determine whether pravastatin reduced the incidence of first or recurrent cardiovascular events in people with non-dialysis-dependent CKD and concomitant diabetes, using data from three randomized trials of pravastatin 40 mg daily versus placebo. CKD was defined by estimated GFR

Background— Statins are important in vascular disease prevention in the elderly. However, the best method of selecting older patients for treatment is uncertain. We assessed the role of plasma lipoproteins as predictors of risk and of treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Method and Results— The association of LDLc and HDLc with risk was examined in the 5804 70- to 82-year-old subjects of PROSPER. Baseline LDLc showed no relation to risk of the primary end point in the placebo group ( P =0.27), nor did on-treatment LDLc in the pravastatin group ( P =0.12). HDLc was inversely associated with risk in subjects on placebo ( P =0.0019) but not in those on pravastatin ( P =0.24). Risk reduction on pravastatin treatment was unrelated to baseline LDLc ( P =0.38) but exhibited a significant interaction with HDLc ( P =0.012). Subjects in the lowest 2 quintiles of HDLc (P P =0.53). During follow-up, there was no relation between achieved level of LDLc or HDLc and risk. However, the change in the LDLc/HDLc ratio on statin treatment appeared to account for the effects of therapy. Conclusions— In people >70 years old, HDLc appears to be a key predictor of risk and of treatment benefit. Findings in PROSPER suggest that statin therapy could usefully be targeted to those with HDLc 3.3.

Lipid abnormalities, which are common in type 2 diabetes, predispose to a greatly increased risk of coronary heart disease. This characteristic dyslipidaemia includes decreased concentrations of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and a small, dense, atherogenic form of low-density lipoprotein cholesterol (LDL-C). Insulin resistance and obesity, which is commonly present in type 2 diabetes, act in concert to disrupt normal lipoprotein metabolism; reverse cholesterol transport in particular. The proatherogenic changes, which result from this process include enrichment of very-low-density lipoprotein with cholesteryl esters and enrichment of LDL with triglycerides. Results from both the Pravastatin Pooling Project and the Heart Protection Study demonstrate that, although people with diabetes obtain the same relative risk reduction with statin therapy, the absolute benefit derived is much lower than for comparable individuals without diabetes. In order to achieve improved outcomes in diabetes patients, it will be important to address other abnormalities in their lipid profiles, including elevated triglycerides and low HDL-C.

Epidemiological studies have associated low HDL-cholesterol with an increased risk of morbid coronary events. Accordingly, intervention to correct low HDL-cholesterol may be cardioprotective. A number of randomized intervention studies have addressed this hypothesis using fibrates (the Veterans Affairs HDL Intervention trial, the Helsinki Heart Study, and the Bezafibrate Infarction Prevention trial), or nicotinic acid, alone [Coronary Drug Project (CDP)] or in combination [the HDL Atherosclerosis Treatment Study (HATS) and the Stockholm Ischaemic Heart Disease study (IHD)]. These trials demonstrate conclusively that treatments to increase HDL-cholesterol deliver clinically significant improvements in prognosis. Of these trials, the largest improvement in outcomes occurred in the HATS trial, where the incidence of a combined coronary endpoint (coronary death, non-fatal myocardial infarction, confirmed stroke, or revascularization for worsening ischaemia) was reduced by 60–90% in patients receiving treatment based on nicotinic acid combined with a statin. The benefits of nicotinic acid-based treatment appear to be durable, as significant outcome benefits were visible in the group of patients initially randomized to nicotinic acid in the CDP 15 years after randomization, i.e. 9 years after the end of double-blind treatment. The combination of nicotinic acid with a statin appears to be a rational, effective, and safe strategy for minimizing cardiovascular risk in patients with dyslipidaemia.

We examined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome and whether it predicted incident diabetes independently of routinely measured factors in 5,974 men in the West of Scotland Coronary Prevention Study. A total of 139 men developed new diabetes over 4.9 years of follow-up. ALT, but not aspartate aminotransferase, levels increased progressively with the increasing number of metabolic syndrome abnormalities from (means ± SD) 20.9 ± 7.6 units/l in those with none to 28.1 ± 10.1 units/l in those with four or more (P < 0.001). In a univariate analysis, men with ALT in the top quartile (ALT ≥29 units/l) had an elevated risk for diabetes (hazard ratio 3.38 [95% CI 1.99–5.73]) versus those in the bottom quartile (

Background Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. Methods We randomly assigned 6595 men, 45 to 64 years of age, with a mean (±SD) plasma cholesterol level of 272±23 mg per deciliter (7.0±0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. Results Pravastatin lowered plasma cholesterol levels by 20 percent and low-density lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death fro...

The safety and tolerability of rosuvastatin were assessed (as of August 2003) using data from 12,400 patients who received 5 to 40 mg of rosuvastatin in a multinational phase II/III program, which represented 12,212 patient-years of continuous exposure to rosuvastatin. An integrated database was used to examine adverse events and laboratory data. In placebo-controlled trials, adverse events, irrespective of causality assessment, occurred in 57.4% of patients who received 5 to 40 mg of rosuvastatin (n = 744) and 56.8% of patients who received placebo (n = 382). In fixed-dose trials with comparator statins, 5 to 40 mg of rosuvastatin showed an adverse event profile similar to those for 10 to 80 mg of atorvastatin, 10 to 80 mg of simvastatin, and 10 to 40 mg of pravastatin. Clinically significant elevations in alanine aminotransferase (>3 times the upper limit of normal) and creatine kinase (>10 times the upper limit of normal) were uncommon ( 10 times the upper limit of normal with muscle symptoms) that was possibly related to treatment occurred in

To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial.After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5 mg, 10 mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6, 10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12.Rosuvastatin 5 mg and 10 mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/Apo A-I) were also reduced significantly by both rosuvastatin doses (p0.001). HDL-C levels increased significantly in the rosuvastatin groups (11% and 8% for 5 mg and 10 mg, respectively, vs. -0.5% for placebo; p0.001), as did Apo A-I levels (p0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported.Rosuvastatin 5 mg or 10 mg once daily is a well-tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components including triglyceride-rich lipoproteins (mainly very low-density lipoproteins [VLDL] and VLDL remnants), LDL-C, and lipoprotein(a). The principal features of the atherogenic lipid profile in type 2 diabetes and the metabolic syndrome make them logical targets for nicotinic acid therapy, either alone or in combination with a statin. The lack of comprehensive European data on the prevalence of low HDL-C levels highlights a critical need for education on the importance of raising HDL-C in CHD prevention and treatment. The development of a reliable and accurate assay for HDL-C, as well as clarification of criteria for low and optimal levels of HDL-C in both men and women, constitute critical factors in the reliable identification and treatment of patients at elevated risk of CHD due to low HDL-C. Based on the available evidence, the European Consensus Panel recommends that the minimum target for HDL-C should be 40 mg/dL (1.03 mmol/L) in patients with CHD or with a high level of risk for CHD, including patients at high global risk with type 2 diabetes or the metabolic syndrome.

Statins cannot always bring plasma lipoprotein levels to target because they only attack one element of the cholesterol homoeostatic pathway. By inhibiting cholesterol absorption as well, using ezetimibe, additional benefits may be obtained. Ezetimibe co-administered with low-dose statin may give an additional 10% reduction in triglyceride, 14% reduction in low-density lipoprotein (LDL) cholesterol, and a 5% rise in high-density lipoprotein (HDL) cholesterol compared to statin alone. In one study, significantly better National Cholesterol Education Program goal achievement was seen with co-administration of ezetimibe and a statin compared to statin treatment alone. Ezetimibe plus a statin is generally well tolerated.

Statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals but their efficacy and safety in elderly people has not been confirmed. Several clinical trials including the Cholesterol and Recurrent Events (CARE) and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), have sub-analysed their results for the 'elderly' cohort, but the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial is the first trial to specifically evaluate the benefits of statin therapy on vascular risk in elderly men and women. The results have shown that pravastatin, given for 3 years, reduced the risk of coronary heart disease in elderly individuals. Within this same time frame, there was no significant benefit on the risk reduction of stroke but there was a trend to reduce the risk of transient ischemic attacks. It was discovered that those patients with the lowest baseline high-density lipoprotein cholesterol gained the most benefit from the intervention. Drug interactions between pravastatin and the concomitant medications seen in this elderly cohort, was not a significant clinical issue. Therefore, PROSPER extends to elderly individuals the treatment strategy currently used in middle-aged people.

Guidelines aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making. A great number of guidelines have been issued in recent years by different organizations-European Society of Cardiology (ESC), American Heart Association (AHA), American College of Cardiology (ACC), and other related societies. By means of links to web sites of National Societies several hundred guidelines are available. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing guidelines. In spite of the fact that standards for issuing good quality guidelines are well defined, recent surveys of guidelines published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilization of health resources. In addition, the legal implications of medical guidelines have been discussed and examined, resulting in position documents, which have been published by a specific Task Force. The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these guidelines or statements. The rationale for an active approach to the prevention of cardiovascular diseases (CVD) is …

See doi:10.1016/S1095-668X(02)00807-2for the articles to which this editorial refers Every day we consume approximately 300mg of cholesterol and its esters and 100g of triglyceride in our diet.1 This mixes in the intestinal lumen with about 900mg of biliary cholesterol and thereafter the total package is reduced by digestion to free cholesterol, fatty acids and mono- and diglycerides which become incorporated, through the detergent effects of bile acids, into water soluble micellesfor transport to absorption sites on the luminal surfaces of small intestinal enterocytes (Fig. 1). Triglyceride absorption is virtually complete whereas only about 50% of the cholesterol finds its way into the intestinal mucosa, the remainder being lost in the faeces. Within the enterocyte, cholesteryl esters are rapidly reconstructed by the action of the enzyme acyl Coenzyme A cholesterol acyltransferase (ACAT) and incorporated, with triglyceride, into large lipid-rich chylomicron particles containing about 1% protein. These appear in abundance in the intestinal mucosal cells following a fatty meal and are transported through omental lacteals to the thoracic duct from which they ultimately spill into the bloodstream via the left subclavian vein. Their onward journey through the systemic circulation exposes them to lipoprotein lipase within adipose tissue and striated (skeletal and cardiac) muscle. This enzyme mobilises and delivers the energy-rich triglyceride fuel to these sites, leaving behind a potentially atherogenic cholesteryl ester-containing remnant, which optimally, is rapidly assimilated by the liver via a specific and highly efficient receptor-mediated process. The half-life of the chylomicron in the circulation is therefore measured in minutes. Fig. 1 Cholesterol homeostasis in man. Each day approximately 1200mg of cholesterol and its esters transits the human intestine, 300mg being derived from dietary sources and 900mg from endogenous synthesis. Following deacylation by cholesterol esterase, the liberated cholesterol becomes incorporated into bile acid-rich micelles, which present it for absorption to …

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.